Clinical evidence has convincingly shown that the BRAF inhibitors (BRAFi) like vemurafenib induce objective tumor regression in >50% of patients with metastatic melanoma that bear the V600E BRAF mutation. However, the tumor regressions are infrequently complete and disease progression occurs at a median of 6-7 months of treatment. Multiple mechanism(s) have been found to support the intrinsic and acquired resistance of melanoma cells to BRAFi and represent major limitations to the use of BRAFi as a single agent in patients with advanced melanoma. Therefore, it is now critical to define combinatorial strategies to eradicate BRAFi sensitive and resistant melanoma cells. In this proposal we will test the hypothesis that BRAFi (vemurafenib) enhances the therapeutic efficacy of IFN?-2b in patients with metastatic melanoma. This hypothesis stems from our novel findings that BRAFi: 1) enhances the sensitivity of melanoma cells to IFN?-mediated anti-proliferative and proapoptotic activity;2) increases T cell-mediated immune responses to melanoma cells by upregulating tumor antigen presentation and downregulating the expression of inhibitory receptor ligand by melanoma cells and;3) prolongs the survival of melanoma bearing mice. These findings reflect an increased IFN?-2b sensitivity of melanoma cells harboring BRAF mutations upon treatment with BRAFi. To assess the clinical significance of our experimental data, the proposed Specific Aims will test the following hypotheses: 1) The administration of BRAFi and IFN?-2b to patients with metastatic melanoma is safe, non toxic and immunogenic;2) The administration of BRAFi enhances the antiproliferative and proapoptotic activity of the of IFN?-2b as well as its ability to upregulate the expression of HLA class I APM component expression by melanoma cells and;3) The administration of BRAFi and IFN?-2b increases tumor antigen (TA)-specific T cell expansion and function in the tumor microenvironment. The information derived from the outlined studies will conthbute to determine the therapeutic relevance of the BRAFi/IFN?-2b combination and the molecular mechanisms underlying its therapeutic effects.
This proposal will test the safety and efficacy of a novel combinatorial therapy with high dose Interferon and Braf inhibitor (vemurafenib). This project may prove critical forthe design of potent targeted combinatorial strategies including Braf inhibitor and high dose interferon for patients with melanoma in the therapeutic or adjuvant setting.
|Dulmage, B O; Feng, H; Mirvish, E et al. (2015) Black cat in a dark room: the absence of a directly oncogenic virus does not eliminate the role of an infectious agent in cutaneous T-cell lymphoma pathogenesis. Br J Dermatol 172:1449-51|
|Sabbatino, Francesco; Wang, Yangyang; Wang, Xinhui et al. (2014) PDGFR? up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget 5:1926-41|
|Tarhini, Ahmad A; Edington, Howard; Butterfield, Lisa H et al. (2014) Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One 9:e87705|
|Ng, Yuen-Keng; Lee, Jia-Ying; Supko, Kathryn M et al. (2014) Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment. Melanoma Res 24:207-18|
|Tarhini, Ahmad A; Shin, Donghoon; Lee, Sandra J et al. (2014) Serologic evidence of autoimmunity in E2696 and E1694 patients with high-risk melanoma treated with adjuvant interferon alfa. Melanoma Res 24:150-7|
|Pancoska, Petr; Kirkwood, John M; Bouros, Spyros et al. (2014) A new mathematical model for the interpretation of translational research evaluating six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon. PLoS One 9:e86375|
|Tarhini, Ahmad A; Lin, Yan; Yeku, Oladapo et al. (2014) A four-marker signature of TNF-RII, TGF-?, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma. J Transl Med 12:19|
|Geskin, Larisa J; Akilov, Oleg E; Lin, Yan et al. (2014) Distinct age-matched serum biomarker profiles in patients with cutaneous T-cell lymphoma. Exp Dermatol 23:598-600|
|Schowalter, Michael K; Dulmage, Brittany O; Ho, Jonhan et al. (2014) Comparative proteomic analysis reveals unique tumor protein composition among the melanoma subtypes pure desmoplastic and superficial spreading. Melanoma Res 24:397-400|
|McArthur, Grant A; Chapman, Paul B; Robert, Caroline et al. (2014) Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 15:323-32|
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